Fangchinoline alleviates atypical hyperplasia of metaplastic ducts and pancreatic fibrosis in caerulein-induced mice.

BACKGROUND

Chronic pancreatitis (CP) is a progressive fibro-inflammatory disease in which acinar-to-ductal metaplasia (ADM) and fibrosis form a vicious cycle, representing an early event in pancreatic carcinogenesis. Fangchinoline, a bisbenzylisoquinoline alkaloid from Stephania tetrandra, exhibits anti-inflammatory and anti-fibrotic properties, although its role in ADM-fibrotic lesions remains unknown yet.

OBJECTIVE

To investigate the effects of fangchinoline on atypical hyperplasia of metaplastic ducts and pancreatic fibrosis, and to clarify its underlying mechanisms.

METHODS

Network pharmacology, bioinformatics, molecular docking, dynamics simulations, and cellular assays were used to elucidate and verify the underlying mechanisms. A C57BL/6 J mouse model was used to elucidate the effects, hepatotoxicity, nephrotoxicity, and cardiotoxicity of fangchinoline.

RESULTS

Fangchinoline alleviated caerulein-induced atypical hyperplasia of metaplastic ducts (64.3%) and reduced pancreatic fibrosis (70.8%). In terms of molecular mechanisms, it targeted bound to the kinase domains of proto-oncogene tyrosine-protein kinase SRC (SRC) and receptor tyrosine-protein kinase ERBB-2 (ERBB2), suppressed their phosphorylation, blocked the downstream focal adhesion kinase (FAK)/zinc finger E-box binding homeobox 1 (ZEB1) signalling, reversed epithelial-mesenchymal transition (EMT), attenuated cancer stemness properties, and reduced the secretion of pro-fibrotic factors. These actions disrupted the vicious cycle between ADM and fibrosis.

CONCLUSION

Fangchinoline is a promising multi-target therapeutic candidate for atypical hyperplasia of metaplastic ducts and pancreatic fibrosis.